Xenotransplantation is generally considered the most likely near-term solution to the major limitation imposed on the field of transplantation today by the severe shortage of cadaver donor organs. For a variety of reasons, the pig now appears to be the donor species of choice, and miniature swine, developed in this laboratory, have several advantages as potential xenograft donors. Because the immune response to such discordant transplantation is exceedingly strong the success of clinical xenografting is likely to depend, at least in part, on finding ways of inducing specific hyporesponsiveness, or tolerance, rather than relying entirely on non-specific immunosuppression. In this Program Project grant we will utilize a large animal pig to primate model to study and overcome the major pediments to such discordant xenotransplantation, and will emphasize the induction of tolerance as a major part of the approach. We will concentrate on four major areas, each constituting the basis of a component grant of the program: 1) avoiding the return of natural antibodies or the effects thereof; 2) producing durable tolerance at the T Cell level; 3) avoiding coagulopathy following xenogeneic transplantation; and 4) understanding and managing the potential infectious disease problems associated with xenotransplantation. All of these projects are highly interactive, and utilize numerous shared resources, many of which will be made available through the large animal core. The work will be carried out in a unique environment, which provides interactions with scientists working in basic and cellular immunology and working on relevant small animal models in the same research center, as well as with clinicians committed to taking new therapies to clinical applications.